EP0143333B1 - (Bis(hydroxymethyl)methyl)-isochinolinderivate, Verfahren zu ihrer Herstellung und pharmazeutische Zubereitungen, die sie enthalten - Google Patents

(Bis(hydroxymethyl)methyl)-isochinolinderivate, Verfahren zu ihrer Herstellung und pharmazeutische Zubereitungen, die sie enthalten Download PDF

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Publication number
EP0143333B1
EP0143333B1 EP84112856A EP84112856A EP0143333B1 EP 0143333 B1 EP0143333 B1 EP 0143333B1 EP 84112856 A EP84112856 A EP 84112856A EP 84112856 A EP84112856 A EP 84112856A EP 0143333 B1 EP0143333 B1 EP 0143333B1
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EP
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Prior art keywords
methyl
hydroxymethyl
bis
formula
dihydroisoquinoline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP84112856A
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English (en)
French (fr)
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EP0143333A1 (de
Inventor
Gábor Dr. Dipl.-Chem. Bernáth
Jenö Dr. Kóbor
Ferenc Dr. Dipl.-Chem. Fülöp
Elemér Dipl.-Chem. Ezer
György Dr. Dipl.-Pharm. Hajós
Eva Dr. Pálosi
László Dr. Dipl.-Pharm. Dénes
László Dr. Szporny
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Richter Gedeon Vegyeszeti Gyar Nyrt
Original Assignee
Richter Gedeon Vegyeszeti Gyar RT
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Priority to AT84112856T priority Critical patent/ATE34740T1/de
Publication of EP0143333A1 publication Critical patent/EP0143333A1/de
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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, ***e
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms

Definitions

  • the invention is concerned with new [bis(hydroxymethyl)-methyl]-isoquinoline derivatives as well as with a process for preparing them and pharmaceutical compositions, particularly with neuroleptic and anticonvulsive activity, containing these compounds.
  • the problem underlying to the invention is to create novel [bis(hydroxymethyl)-methyl]-isoquinoline derivatives having valuable pharmacological effects and further serving as intermediates for preparing other isoquinoline derivatives having valuable pharmacological properties, a process for preparing them and pharmaceutical compositions containing them.
  • the subject-matter of the invention are [bis(hydroxymethyl)-methyl]-isoquinoline derivatives of the formula (I) wherein
  • the subject-matter of the invention is also a process for preparing the compounds according to the invention which is characterized in reacting a 1-methyl-3,4-dihydroisoquinoline of the formula (II) or a 1-((3-hydroxyethyl)-3,4-dihydroisoquinoline of the formula (III) wherein R 1 and R 2 are as defined above, with formaldehyde, the hydrate or trimeric derivative thereof, then, if desired, hydrogenating a bis[(hydroxymethyl)-methyl]-3,4-dihydroisoquinoline derivative of the formula (IV) obtained, wherein R 1 and R 2 are as defined above, and/or, if desired a compound of the generic formula I obtained, wherein R 1 and R 2 are a C 1-6 alkoxy group, is converted by dealkylation into a compound of the generic formula I containing as R 1 and R 2 a hydroxyl group, and/or, if desired, a compound of the generic formula I obtained, wherein R 1 and R 2
  • the 1-methyl- and 1-( ⁇ -hydroxyethyl)-isoquinoline derivatives of the formulae (II) and (III) used as starting materials, in which R 1 and R 2 are as defined above, are known in the art, and can for example be prepared from homoveratryl amine or the corresponding ⁇ -phenylethyl amine derivative by acetylation and a subsequent ring closure conventionally used for preparing isoquinoline compounds, e.g. Bischier-Napieralski synthesis.
  • the hydrate or trimeric derivative thereof i.e. paraformaldehyde or trioxane, which are commercially available materials.
  • the reaction is preferably carried out in alkaline medium, most preferably in the presence of an alkali metal alcoholate or alkali metal hydroxide.
  • an alkali metal alcoholate for example sodium methylate or sodium ethylate
  • an alkali metal hydroxide for example sodium or potassium hydroxide is employed.
  • the starting compounds of the formulae (II) and (III) are preferably reacted with formaldehyde and derivatives thereof in an inert organic solvent, such as an alcohol having from 1 to 6 carbon atoms, e.g. methanol; or in an aromatic hydrocabron, e.g. benzene.
  • an inert organic solvent such as an alcohol having from 1 to 6 carbon atoms, e.g. methanol; or in an aromatic hydrocabron, e.g. benzene.
  • Formaldehyde and derivatives thereof may be used in an equimolar amount related to the starting compounds, or in a slight excess.
  • a small amount of a 1-((3-hydroxyethyl)-isoquinoline derivative can also be isolated as a by-product, which can easily be separated from the main product, e.g. by recrystallization from ether.
  • the reaction temperature may be varied within wide limits, but preferably it is between room temperature and the reflux temperature. Most preferably the reaction is carried out around room temperature.
  • the reaction time is a function of temperature and other reaction conditions, e.g. the reactants and medium employed, and generally amounts to several hours.
  • Hydrogenation can be performed with any conventional hydrogenating agent, such as a complex metal hydride or with hydrogen in the presence of a catalyst.
  • a complex metal hydride for example sodium-tetrahydroborate (III) or lithium-aluminium hydride is employed.
  • Catalytic hydrogenation is carried out under normal conditions, preferably in ethanol, in the presence of a catalyst conventionally used for hydrogenation, e.g. palladium-on-charcoal or platinum oxide.
  • Salt formation can be carried out in an inert organic solvent, for example in a C 1 - e aliphatic alcohol, by dissolving the compound of the formula (I) in the solvent and the selected acid or by adding a solution thereof formed with the same solvent to the first solution until it becomes slightly acidic (pH 5 to 6). Thereafter the acid addition salt separates out and may be removed from the reaction mixture e.g. by filtration.
  • an inert organic solvent for example in a C 1 - e aliphatic alcohol
  • the compounds of the formula (I) or the salts thereof, if desired, can be subjected to further purification, e.g. recrystallization.
  • the solvents used for recrystallization are selected depending on the solubility and crystallization properties of the compound to be crystallized.
  • the substituents R 1 and/or R 2 can easily be converted into other substituents within the definition of R 1 and R 2.
  • compounds of the formula (I) in which R 1 and/or R 2 is hydroxyl can be converted into the corresponding compounds of the formula (I), in which R 1 and/or R 2 represent an alkoxy group having from 1 to 6 carbon atoms, by methods known in the art.
  • the 6,7-dimethoxy compounds are most expediently prepared by methylation of the corresponding 6,7-dihydroxy compounds with diazomethane or dimethyl sulfate.
  • the higher ethers can for example be prepared by the Wiliamson synthesis, using alkyl iodides.
  • R 1 and/or R 2 represent an alkoxy group having from 1 to 6 carbon atoms
  • the corresponding compounds containing hydroxyl as R 1 and/or R 2 can be obtained by known reactions, e.g. heating with hydrogen bromide or hydrogen iodide or by means of anhydrous aluminium chloride.
  • compositions which contain one or more compound(s) according to the invention as [an] active ingredient(s), suitably together with one or more pharmaceutical carrier(s) and/or excipient(s), are provided for.
  • the compounds according to the invention are pharmaceutically active, e.g. show neuroleptic and anticonvulsive activity.
  • the compounds according to the invention are further useful intermediates in the preparation of other pharmaceutically active isoquinoline derivatives.
  • they can be converted into various pharmaceutically active N-substituted [bis(hydroxymethyl)-methyl]-isoquinoline derivatives having for example immunsuppressive, anticonvulsive, analgesic or antipyretic activity, by conventional techniques of N-substitution. Further details of this process are disclosed in the European Patent Application 84 112 855.6, published under the number EP ⁇ A ⁇ 142 740. Further valuable compounds are obtained if in the compounds of the formula (I) one or both hydroxyls of the bis(hydroxymethyl)-methylene group are replaced by other substituents, e.g. acyl groups.
  • Example 1 The procedure described in Example 1 is followed except that instead of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline an equivalent amount of 1-methyl-6,7-diethoxy-3,4-dihydroisoquinoline is used as a starting material. Evaporation of the reaction mixture under reduced pressure and recrystallization of the crude product obtained from benzene yields the aimed compound.
  • Example 2 Following the procedure described in Example 1 but replacing sodium ethylate by an equivalent amount of sodium methylate at a catalyst, the aimed compound is obtained, which has the same melting point as given in Example 1:
  • Example 2 Following the procedure described in Example 1 but replacing sodium ethylate by an equivalent amount of sodium hydroxide as a catalyst, the aimed compound is obtained which has the same melting point as the product obtained in Example 1.
  • Example 1 0.1 mole of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-3,4-dihydroisoquinoline obtained in Example 1 is dissolved in 180 ml of absolute ethanol, and then a 1.5-fold excess of dry hydrogen chloride gas dissolved in absolute ethanol is added to the solution. After recrystallization from a mixture of methanol and ether the obtained 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride melts at 181 to 184°C.
  • the 6,7-diethoxy analogue of the above compound can be prepared in an analogous manner, starting from 1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-3,4-dihydroisoquinoline; melting point: 127 to 128°C (benzene).
  • the product obtained does not give any melting point depression when admixed with the product prepared according to Example 10.
  • Reaction time 4 to 6 hours.
  • the product obtained does not give any melting point depression when admixed with the products obtained in Examples 10 and 13.
  • the product obtained has analgesic and antipyretic activity.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Nanotechnology (AREA)
  • Neurology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Physics & Mathematics (AREA)
  • Mathematical Physics (AREA)
  • Theoretical Computer Science (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Transplantation (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
  • Phenolic Resins Or Amino Resins (AREA)

Claims (9)

1. [Bis(Hydroxymethyl)-Methyl]-lsochinolinderivate der Formel (I)
Figure imgb0026
wobei
R1 und R2 ein Hydroxyl oder Alkoxyl mit 1 bis 6 Kohlenstoffatomen darstellen,
R3 für Wasserstoff oder ein einzelnes Elektronenpaar steht und die gestrichelte Linie eine mögliche zweite Bindung darstellt, und seine Salze.
2. [Bis(Hydroxymethyl)-Methyl]-isochinolinderivate gemäß Anspruch 1, dadurch gekennzeichnet, daß das Alkoxyl, das durch R1 und/oder R2 dargestellt sein kann, so ausgebildet ist, daß es 1 oder 2 Kohlenstoffatome aufweist.
3. [Bis(Hydroxymethyl)-Methyl]-isochinolinderivate, ausgewählt aus der Gruppe von
1-[Bis(Hydroxymethyl)-Methyl]-6,7-Dimethoxy-3,4-Dihydroisochinolin und seinen Säureanlagerungssalzen,
1-[Bis(Hydroxymethyl)-Methyl]-6,7-Diethoxy-3,4-Dihydroisochinolin und seinen Säureanlagerungssalzen,
1-[Bis(Hydroxymethyl)-Mefhyl]-6,7-Dihydroxy-3,4-Dihydroisochinolin und seinen Säureanlagerungssalzen,
1-[Bis(Hydroxymethyl)-Methyl]-6,7-Dimethoxy-1,2,3,4-Tetrahydroisochinolin und seinen Säureanlagerungssalzen und
1-[Bis(Hydroxymethyl)-Methyl]-6,7-Diethoxy-1,2,3,4-Tetrahydroisochinolin und seinen Säureanlagerungssalzen.
4. Ein Verfahren zur Herstellung der Verbindungen gemäß der Ansprüche 1 bis 3, gekennzeichnet durch die Umsetzung eines 1-Methyl-3,4-Dihydroisochinolins der Formel (II)
Figure imgb0027
oder eines 1-(ß-Hydroxyethyl)-3,4-Dihydroisochinolins der Formel (III)
Figure imgb0028
wobei R1 und R2 wie oben festgelegt sind, mit Formaldehyd, seinem Hydrat oder Trimerderivat, sodann ggf. durch Hydrierung eines erhaltenen [Bis(Hydroxymethyl)-Methyl]-3,4-Dihydroisochinolinderivats der Formel (IV)
Figure imgb0029
wobei R1 und R2 wie oben festgelegt sind, und/oder ggf. durch Umwandlung einer erhaltenen Verbindung der allgemeinen Formel I, wobei R1 und R2 eine C1-6-Alkoxylgruppe darstellen, durch die Alkylierung in eine Verbindung der allgemeinen Formel I, die R1 und R2 als Hydroxylgruppe enthält, und/oder ggf. einer erhaltenen Verbindung der allgemeinen Formel I, wobei R1 und R2 Hydroxylgruppen darstellen, in eine entsprechende Verbindung, die R1 und R2 als C1-6-Alkoxylgruppe enthält, und/oder ggf. durch Umwandlung einer erhaltenen Verbindung der Formel (I) in ihr Salz oder durch Umwandlung eines Salzes der erhaltenen Verbindung der Formel (I) in die entsprechende freie Base der Formel (I) und/oder in ein anderes Salz.
5. Ein Verfahren gemäß Anspruch 4, dadurch gekennzeichnet, daß die Reaktion einer Verbindung der Formel (II) oder (III) mit Formaldehyd, seinem Hydrat oder Trimerderivat in einem Alkalimedium ausgeführt wird.
6. Ein Verfahren gemäß Anspruch 4 oder 5, dadurch gekennzeichnet, daß die Reaktion in Gegenwart eines Alkalimetallalkoholats als alkalischem Mittel durchgeführt wird.
7. Ein Verfahren gemäß einem der Ansprüche 4 bis 6, dadurch gekennzeichnet, daß die Hydrierung eines Bis(Hydroxymethyl)-Methyl-3,4-Dihydroisochinolinderivats der Formel (IV) mit einem komplexen Metallhydrid oder mit katalytischer Hydrierung durchgeführt wird.
8. Arzneimittel, gekennzeichnet durch einen Gehalt an einer oder mehreren Verbindung(en) gemäß der Ansprüche 1 bis 3 als (einen) aktive(n) Bestandteil(e), zweckmäßigerweise zusammen mit einem oder mehreren pharmazeutischen Träger(n) und/oder Zusatzstoff(en).
EP84112856A 1983-10-25 1984-10-25 (Bis(hydroxymethyl)methyl)-isochinolinderivate, Verfahren zu ihrer Herstellung und pharmazeutische Zubereitungen, die sie enthalten Expired EP0143333B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT84112856T ATE34740T1 (de) 1983-10-25 1984-10-25 (bis(hydroxymethyl)methyl)-isochinolinderivate, verfahren zu ihrer herstellung und pharmazeutische zubereitungen, die sie enthalten.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU365183 1983-10-25
HU833651A HU189348B (en) 1983-10-25 1983-10-25 Process for producing l-/bis/hydroxy-methyl/-methyl/-3,4-dihydro- or 1,2,3,4-tetrahydro-isoquinolin derivatives

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EP0143333A1 EP0143333A1 (de) 1985-06-05
EP0143333B1 true EP0143333B1 (de) 1988-06-01

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US (1) US4656179A (de)
EP (1) EP0143333B1 (de)
JP (1) JPS60132961A (de)
AT (1) ATE34740T1 (de)
CA (1) CA1237432A (de)
DE (1) DE3471654D1 (de)
DK (1) DK508384A (de)
FI (1) FI79100C (de)
HU (1) HU189348B (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU189348B (en) * 1983-10-25 1986-06-30 Richter Gedeon Vegyeszeti Gyar Rt.,Hu Process for producing l-/bis/hydroxy-methyl/-methyl/-3,4-dihydro- or 1,2,3,4-tetrahydro-isoquinolin derivatives
US10361802B1 (en) 1999-02-01 2019-07-23 Blanding Hovenweep, Llc Adaptive pattern recognition based control system and method
US8352400B2 (en) 1991-12-23 2013-01-08 Hoffberg Steven M Adaptive pattern recognition based controller apparatus and method and human-factored interface therefore
US7966078B2 (en) 1999-02-01 2011-06-21 Steven Hoffberg Network media appliance system and method

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1036420A (en) * 1964-09-22 1966-07-20 Roche Products Ltd Medicinally useful isoquinoline derivatives and pharmaceutical preparations containing same
GB1386076A (en) * 1971-06-03 1975-03-05 Wyeth John & Brother Ltd Isoquinoline derivatives
HU189348B (en) * 1983-10-25 1986-06-30 Richter Gedeon Vegyeszeti Gyar Rt.,Hu Process for producing l-/bis/hydroxy-methyl/-methyl/-3,4-dihydro- or 1,2,3,4-tetrahydro-isoquinolin derivatives

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DE3471654D1 (en) 1988-07-07
FI79100C (fi) 1989-11-10
US4656179A (en) 1987-04-07
DK508384D0 (da) 1984-10-25
CA1237432A (en) 1988-05-31
FI844184A0 (fi) 1984-10-25
HU189348B (en) 1986-06-30
EP0143333A1 (de) 1985-06-05
ATE34740T1 (de) 1988-06-15
JPH0414664B2 (de) 1992-03-13
DK508384A (da) 1985-04-26
FI79100B (fi) 1989-07-31
JPS60132961A (ja) 1985-07-16
FI844184L (fi) 1985-04-26

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